1. Three Common Neonatal Infections: 2013 Roger G. Faix, M.D. The University of Utah Primary Children’s Medical Center Intermountain Medical Center

2. Importance of Cytomegalovirus (CMV) n Frequent pathogen in all human populations u 70-80% of US adults are seropositive u Up to 100% in the developing world

3. Importance n Transmission usually involves prolonged intimate contact with infected body fluid n Infection ≠ Disease – usually asymptomatic in immunocompetent subjects n Among immunocompromised, CMV is a leading cause of morbidity and mortality

4. Cytomegalovirus CPE In Vivo

5. CMV n One of at least 8 human herpesviruses u DNA genetic material u Latency – lifelong potential dormancy u Persistence – may shed virus for years u Reactivation- latent virus may become actively shed again

6. Importance n Congenital infection (acquired in utero, present at birth): 0.5 – 2.5% of liveborns, (10,000-50,000/year in US) n Natal infection (acquired during passage through infected birth canal): 10-35% of liveborns; detectable after 3 weeks n Post-natal infection (acquired after birth): up to 100% in some populations; breast milk, day care, contact with infected fluid

7. Importance n Natal and postnatal infections usually are asymptomatic in newborns, but u VLBWs may develop sepsis-like condition and other syndromes u May cause significant disease if subject later immunocompromised u May serve as a source for transmission to high risk individuals

8. Importance of Congenital CMV n Major cause of morbidity and death for embryo, fetus, and neonate n Wide array of potential responsible agents for congenital infection - important to identify which responsible n CMV most common cause of congenital infection in US by far

9. Congenital CMV Infection

11. n Potential for intervention n Limitations of therapy u Effective therapy may arrest further injury, BUT u May not reverse injury that already occurred u May not immediately stop injury

12. Congenital Cytomegalovirus (CMV) n Mother usually asymptomatic n Transmission from mother to fetus hematogenous or transamniotic n Father may be source of infection or multiple other sources n DNA analysis useful for epidemiologic investigations

13. Congenital Cytomegalovirus (CMV) n With congenital CMV infection, symptomatic disease occurs in 5-10% n With symptomatic presentation, 90+% will have severe neurodevelopmental sequelae (100% if microcephaly or intracranial destructive lesions)

14. Symptomatic Presentation n Abnormal head size n CNS lesions n Calcifications n Organomegaly n Adenopathy n Petechiae n ‘Blueberry muffin’ n Symmetric IUGR n Hydrops n Anemia n Bony/dental lesions n Deafness n Chorioretinitis n Numerous others

15. Congenital CMV

17. Congenital Cytomegalovirus (CMV) n With congenital CMV infection, 90%+ are usually asymptomatic at birth u 10-15% of these may develop later sequelae, usually relatively mild Hearing loss (SNHL) Hearing loss (SNHL) Enamel hypoplasia Enamel hypoplasia Seizure disorders Seizure disorders Learning disorders Learning disorders

18. Congenital CMV: Hearing Loss >20 dB (Fowler et al, 1999)

19. What Determines Presentation? n Maternal infection – primary or recurrent n Gestational timing of infection n Maternal organism load n Other factors to be determined

20. Congenital Cytomegalovirus (CMV)

21. Effect of GA at primary CMV infection on transmission and disease Outcome4-22 wk GA16-27 wk GA23-40 wk GATotal Maternal primary CMV 33102669 Fetal infection17 (51%)6 (60%)12 (46%)35 (51%) Symptomatic congenital 2 (12%)1 (16%)0 (0%)3/37* (8%) Severe sequelae5 (29%)0 (0%) 5/37* (13%) *32 of original 69 were terminated or otherwise lost before birth

22. Congenital CMV n Much lower risk in mother who is seropositive at start of pregnancy, BUT absolute number of those who are seropositive is so much greater that absolute number of resultant infants with symptomatic CMV is significant n Up to 40% of those with symptomatic congenital CMV result from mothers who were seropositive at start of pregnancy

23. Diagnosis of Congenital CMV n Many other pathogens may cause congenital disease that mimic CMV n It is important to determine the presence/absence of these organisms u Some are amenable to specific therapy u Many are associated with very different sequelae and care needs

24. Diagnosis of Congenital CMV n Viral culture (urine, saliva) up to age 3 weeks – congenital detected more quickly due to high viral load n PCR up to 3 weeks of age OR blood spot from newborn screen

25. Diagnosis of Congenital CMV n TORCH titers - very limited utility u IgG- specific usually transplacental u IgM-specific antibody – diagnostic if + in first 3 weeks; does not exclude if negative

26. Treatment of Congenital CMV n Treat signs/symptoms as detected n Longitudinal assessment for SNHL n Ganciclovir (GCV) u IV 6 weeks; CVC requirement u 50% thrombocytopenia, neutropenia u Does ↓frequency and severity of SNHL u Sparse data re: other CMV issues u Chorioretinitis usually treated

27. Quantity of CMV in urine with 42 days of GCV (Whitley, 1997)

28. Treatment of Congenital CMV n Valganciclovir – oral prodrug converted to GCV upon absorption; sparse neonatal data, but what there is appears promising n Problems with all u Not eradicate latency u Viral infection recurs once stop u Not reverse established injury

29. Utah State Law – 2013 Session n All newborn infants who fail hearing screen must undergo testing for congenital CMV n Parents of all infants found to be positive, must be offered counseling re: treatment, consequences

30. Prevention of Congenital CMV n n Infection control and universal precautions remain critical u u At home, school, hospital, all settings u u High potential (not always avoidable) for contacting infected fluids of asymptomatic, actively shedding individuals

31. Early-onset GBS (EOGBS) in the Era of Intrapartum Antibiotic Prophylaxis IAP)

32. GBS n Although dramatic decreases in frequency since adoption of universal screening and IAP, still #1 cause of early-onset sepsis in term infants in US n Frequent cause of mortality (5-10% of affected) and morbidity

33. EOGBS and ECMO

34. Suspicion aroused, if no IAP and… n No antenatal culture n Culture obtained, but results unavailable n History GBS UTI n History maternal chorioamnionitis n History prior infant with EOGBS n Unexplained POL n ROM >18 hours

35. Suspicion aroused, if IAP given but… n Negative culture may be false-negative n IAP with erythromycin or clindamycin may be ineffective n IAP with penicillin or cefazolin may be ineffective if given <4 hrs prior to delivery

36. EOGBS – Presenting Signs n Temp Instability n Respiratory distress n Neutropenia n Thrombocytopenia n Hypoperfusion n Hypoglycemia n Pneumonia n PPHN n Focal erythema n Arthritis n Meningitis n Others

37. Treatment for EOGBS n Supportive n Culture u Blood u CSF u Focal areas n Empirical treatment u Ampicillin and Gentamicin u If +, covert to PCN G – 400,000U/kg/d

38. Treatment for EOGBS n Follow-up culture to assure sterilization n Duration u 7-10 after sterilization, if + blood only u 14-21 after sterilization, if CSF+ u 14+ after resolution of sequestered focus

39. RSV

40. Respiratory syncytial virus (RSV) n Paramyxovirus: RNA, many strains n Mother or other contacts (family, healthcare staff) symptomatic or mild URI n Spread by contact with respiratory droplets, not aerosol

41. RSV and ECMO

42. Respiratory syncytial virus (RSV) n Neonatal signs: rhinorrhea, wheezing, pneumonia, lethargy, irritability, apnea; in preterms, absent or minimal respiratory signs is not unusual n Diagnosis u culture/PCR u IFA or EIA of NP swab (only 80-90% sensitive)

43. Respiratory syncytial virus (RSV) n Prevention: RSVIg (IM or IV) u Controversial based on cost-benefit analyses, lack of data re: mortality and need for vent u Nonetheless recommended by AAP in select circumstances and widely used, including SLC

44. Respiratory syncytial virus (RSV) n Infection control: u Careful attention to handwashing u Minimizing hand-eye contact u Barrier precautions u Discouraging visiting by infected family, work by infected staff

45. Respiratory syncytial virus (RSV) n Treatment u Supportive u Careful attention to upper airway toilet u Bronchodilators controversial (racemic epi-, albuterol, DXM) u Ribavirin very controversial